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United States Patent Frederick C. Novello, Lansdale, Pa., assignor to Merck & C0,, 'Ine, Rahway, NJ., a corporation of New Jersey e No Drawing. Application July 16, 1957 Serial No. 672,127 r 8 Claims. (Cl. 260-443) This invention comprises novel benzothiadiazine-l,ldioxide compounds containing an amino as well as a sulfamyl substituent attached to the benzenoid portion of V the nucleus.

The structural formula of the new compounds of this invention is illustrated below. In those compounds hav- 'ing no substitution other than hydrogen on either nitrogen 2 ,910,474 Patented Oct. 27, 1959 2 and w zN V 1 N B1 H2NSO2 or these structures can be tautomeric isomers.

The novel benzothiadiazine-l,l-djoxide compounds of this invention therefore comprise compounds having a general structure as illustrated and defined above, and their nontoxic alkali metal salts, wherein R is hydrogen or a lower alkyl radical advantageously containing from 1 to 5 carbon atoms; and R is hydrogen, a lower alkyl preferably having from 1 to 5 carbon atoms, or a mononuclear aryl such as a phenyl, benzyl, styryl and the like or similar radicals substituted in the phenyl moiety by halogen, lower alkyl, or lower alkoxy and the like radicals; a

The new, compounds of this invention as, well as the intermediate nitro compounds are useful pharmacotherapeutic agents particularly because of their diuretic and/ or natriuretic properties. The compounds can be administered in therapeutic dosages in conventional vehicles as in the form of a tablet or capsules as these compounds are efiective uponoral administration as well as upon injection. As the compounds of this invention also are readily soluble in a dilute alkaline medium or in polyethylene glycol solutions, injectable solutions can be prepared by dissolving the desired compound in, the selected medium to which preservatives can be added if desired.

The benzothiadiazine-Ll-dioXides of this invention can be prepared by a variety of methods. Two processes which have been found to be particularly well adapted to 1 N the preparation of compounds containing the amino (or nitro) and sulfamyl substituents in the 6- and 7-positions N respectively can be illustrated as follows:

III 1V R1 I I RNHk 1.1100011 1 nmso SOiNHg 2 A nlNsor /S(&

INEQOH i112 .r t om R NH I L OISO'ZH om R NH 'H N- R 2. Na 1 i o1so S0261 HINSO L \S/ a y t o o I 11 VII luvooho In,

l N om R1NOCR' LNHOH om Tat oiso s0,o1' A Hmso in the presence of an alkali metal halide for'example purposes sodium chloridecan be used as it is readily derivative to the chlorosulfonic' acid dropwise with chloride at a moderate rate. Following this, the mixture in an organic solvent and bubbling ammonia gas into the solution to form the diamide compound. The diamide The process wherein the amino. disulfonyl chloride is v as a sulfonyl chloride substituent attached to the benzefirst converted to the amide, the amide then formylated noid portion of the nucleus. and the compound cyclized' is preferred when it is desired The acylation of Compound II can be carried out at to prepare a benzothiadiazine-1,1-dioxide having no subroom temperature or, if desired, by Warming. At least stituent on the carbon atom in the 3-position. The second 5 a molar equivalent of the acylating compound is emmethod wherein the amino disulfonyl chloride is first ployed in the reaction although an excess of the aeylating acylated, then converted to the amide and subsequently reagent can 'beused ifit is desired to have this reactant cyclized is preferred when a benzothiadiazine-1,1-dioxide serve as a, solvent for Compound II as well, I If because Compound Containing a substituent in the 3-P0Siti0n is to of cost or limited availability of the acylating agent it is be prepared. desired to use another solvent in the reaction mixture,

The chlorosulfonation of Comp und I is Carried out this can, of course, be done. Suitable solvents include benzene, toluene, xylene, dioxane or other inert organic solventswhich will dissolve Compound II without interfering in any way with the acylating reaction.

The acylated Compound V, then can be converted to the corresponding amide by the method described above employing, advantageously, aqueous or alcoholic ammonium hydroxide, liquid ammonia, or ammonia gas and the N-acyl-disulfamyl compound thus obtained is heated sodium, potassium or lithium chloride. For all practical available, cheap, and in its presence the reaction proceeds quite smoothly. As the reaction between these ingredients is quite vigorous, it is preferred to add the aniline stirring and cooling; After all of the aniline derivative "has been added, the alkali metal chloride is added in 0 at betwegn about to about to form the Small portions to allow the evolution hydrogen cyclized product, VI, which also contains a nitro as well as a sulfamyl substituent attached to the benzenoid portion of the nucleus.

The nitro group in the cyclized product, VI then can be converted to the amino group by reduction according to the process described above for reducing Compound IV to Compound VII.

Another process which also has been found to be particularly Well adapted to the preparation of compounds containing the amino (or nitro) and sulfamyl substituents in the 6- and 7-positions respectively and which also contain a substituent other than hydrogen on the 2-position compound then is heated with formic acid or ethyl nitrogen a illustrated as follows:

1. E1: orthoformats 2. A

XII XI The chlorosulfonation of Compound VIII is carried out in substantially the same manner as described above for the chlorosulfonation of Compound I. The 2-amino-5- chloro-4-nitro-benzenesulfonyl chloride thus obtained then is reacted with the selected lower-alkylamine which is employed in an amount in excess of two equivalents and preferably with heating to complete the reaction to form the 4 chloro 2-(N-lower-alkylsulfamyl)-5-nitroaniline. reduced to the corresponding amino group by known This reaction product, X, then is treated with ethyl orthomethods. Reduction advantageously can be effected by formate 'q y in excess of a molar equivalent and catalytic hydrogenation employing platinum or paladium fhi' between to form the cychzfid P as the catalyst. Platinum oxide has been-found t be 'uct, XI, 2 alkyl-7-chloro-6-nitro-1,2,4-benzothiadiazineparticularly suitable f thi d ti l h u h othgr i,l-dioxide. The nitro substituent then can be reduced cataly t h was l i on a carrier, also can be usgd and the chlorine simultaneously removed by the method for the reduction f th it t h amino group to fol-m described above. The2-alkyl-6-amino-compound then is CompoundVII. chlorosulfonated to introduce the 7-sulfonyl chloride Alternatively, the amino disulfonyl chloride compound, group and this p then converted to the sulfamyl II, can be acylated with an organic id hl id stituent by treatment with ammonia by substantially the hydride, the a id advantageously b i l d f a same method described for conversion of the disulfonyl lower alkanoic acid such as acetic acid, propionic acid, 0 chloride COIIIPOUHd 11, t0 the Corresponding disulfamyl oaproic acid and the like, or a mononuclear aryl-monoderivative, thus forming the desired 240W alkyhfi" carboxylic acid such as benzoic acid, phenylacetic acid, amino-7-sulfarnyl-1,2,4-benzothiadiazine-1,l-dioxide. cinnam-ic acid, and the like. This reaction proceeds quite An alternative method for preparing Compound XIII smoothly at room temperature yielding the N-acyl-difrom Compound X comprises heating Compound X with sulfflhyl chloride derivative, V, containing a nitro as well sodium sulfite to term the sodium 4-amino-5-(N-1ower is heated at between about to 200 C. preferably in an oil bath. 1 j

The disulfonyl chloride, II, thus obtained then can be 25 converted to the disulfamyl derivative, III, by treatment with ammonia. The ammonia is employed in excess of that required to form the corresponding aminobenzene disulfonamide and advantageously can be added in the form of .aqueous or alcoholic ammonium hydroxide, liquid ammonia or by dissolving the disulfonyl chloride VIII orthoformate at between-about 100 to C. after which the solvent is removed preferably by distillation thus forming the benzothiadiazine-1,1-dioxide compound, IV,"having a nitro as well as a sulfamyl group attached to the benzenoid position of the nucleus. The formic acid or the ethyl orthoformate is used in quantity in excess of a molar equivalent.

The nitro substituent in Compound IV then can be u alkylsulfamyl) -2-nitrobenzenesulfonate. This product with water and dried over sodium sulfate. After rethen can be treated with chlorosulfonic acid and then moval of ether on the steam bath, the residual S-nitrowith ammonia by the process described above for conaniline-2,4'disulfonyl chloride is obtained. This product verting Compounds. I and II to the sulfamyl derivative is cooled in an ice bath and treated with 150 ml. of 28% thus forming Z-N-alkyIsuIfamyl S-nitro-4-sulfarnylaniline ammonium hydroxide in a Zliter Erlenmeyer flask. The

which, upon treatment with ethyl orthoformate by the mixture is heated on the steam bath for 1 hour, cooled process described above and then heating is cyclized to and the product collected on the filter, washed with the 2 alkyl-6-nitro-7-sulfamyl-1,2,4-benzothiadiazine-1,1- Water and dried. Upon crystallization from dilute aldioxide. This cyclized product then can be reduced to cohol, 2,4-disulfamyl-5-nitroaniline is obtained as colorconvert the nitro to the amino derivative, XIII. less needles, melting point 260262 C.

A fourth novel process for preparing the compounds Analysis calculated for C H N O S C, 24.32; H, 2.72; of this invention, particularly those wherein the amino N, 18.91. Found: C, 24.53;'H, 2.71; N, 19.11. (or nitro) and sulfamyl substituents are attached to the Step b.A solution of 5 g. of 2,4-disulramyl-5-nitro- 7- and -positions respectively can be illustrated as folaniline in 175 ml. of 98-100% formic acid is heated lows: under reflux for 3 hours. After thorough cooling, the

01-- NH; Nazsoa NaOS-r NH; L CISOSH C1820 NH,

e NOr- A NOr- N801 NO soio1 XIV XV XVI lNH OH nmsm- W HzNSO HCOOH H2Nsor- NH,

H NH N0 NE T NO soNn:

\r. r s.

XIX XVIII I XVII The 3-chloro-4-nitroaniline intermediate in this process colorless needles are collected on the filter, washed With is converted to the sodium S-amino-Z-nitrobenzenesulfoalcohol, and dried yielding 6-nitro-7-sulfamyl-1,2,4-ben nate by heating the aniline compound, preferably under zothiadiazine-1,1-dioxide, melting point 338339 C. with reflux, with sodium sulfite. An excess of sodium sulfite decomposition. dissolved in water is'advantageously employed in this re- Analysis calculated for C I-I N 0 S C, 27.45; H, 1.98; action. The reaction product thus obtained, XV, then is N, 18.30. Found: C, 27.73; H, 2.28; N, 18.17. chlorosul fonated, converted to the disulfamyl derivative, 7 Step c.--A solution of 2.7 g. of the thus obtained 6- XVII, and then cyclized and the nitro substituent can he nitro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide in 600 reduced to the corresponding amino by the process deml. of a 50% alcohol-water mixture is shaken in an atscribed above for preparing Compounds II, III, IV, and mosphere of hydrogen with 400 mg; of platinum oxide VII thus forming 7-a1nino (or nitro)-6sulfarnyl-l,2,4- 40 catalyst until hydrogen absorption ceases. Thecatalystbenzothiadiazine-l,l-dioxide. is removed by filtration and the solution concentrated to The alkali metal salts of the benzothiadiazine-1,1- dryness in vacuo. Crystallization of the residue from a dioxide compounds ofthis invention can be prepared by 50% alcohol-water mixture yields 6-amino-7-sulfamyldissolving the selected compound in an aqueous or alco- 1,2.4-be11Z0fl1iadiflZine-1,l-dioXide Colorless needles, holic solution of the alkali metal hydroxide, and, if demelting point 323324 C. with decomposition. sired, isolating the salt by evaporating the solvent. Any alysis Calculated for C H N O S C, 30.43; H, 2.92; of the conventional alkali metal salts, such as the sodium, Foulldi .20.16- potassium, lithium or the like salt, can be prepared by EXAMPLE 2 this method or by other methods known to organic chemists 6-amm0-3-methyl-7-sulfamy[-1,2,4-benz0thiadiazine-I,1-

The amino substituted benzothiadiazine-1,l-dioxide dioxide compounds of this invention, as well as the correspond- Step l.A solution of 5.0 g. of 5-nitroaniline-2,4-diing intermediate nitro compounds are new compounds sulfonyl chloride, obtained as described in step a, Exand both of these series of compounds possess diuretic ample l, in 15 ml. of acetic anhydride is allowed to stand d/ natriflpetic ppcperties at room temperature for 45 minutes. After cooling, the The preparation of these compounds is more fully de- Crystalline P y l 3 ib d i h f llowin examples, i i to d chloride, is collected, treated with 50 ml. of 10% alcoholic stood, however, that the examples are illustrative of the ammonia and evaporated to d y 0H thfisteam bathcompounds embraced by this invention and of the meth- The residueois heated 2 0 hour, Cooled ods for their preparation and are not to be construed l crystalllzed from a g q to hy as limiting the invention to particular compounds or n1tro-7-sulfamyl-1,2,4-benzoth1ad1az1ne-1,l-dioxide. methods specifically described. I Step b.- A solution of 3.0 g. of the product obtained in step a in 600 ml. of a 50% alcohol-water mixture is EXAMPLE 1 shaken in an atmosphere of hydrogen with 400- mg. of

6-amin0-7-sulfamyl-1,2,4-benz0thiadiazine-1,1-di0xide Blatmum oxlfle Catalyst untll hyd rogen p ion ased.

. i I 1 the catalyst 1s removed by filtratlon and the solution con- P a-m-Nltroanll lfle mole) 1S aflded centrated to dryness in vacuo. Crystallization of the dropwise with stirring to 375 ml. of'chlorosulfonic acid residue f om a 50% alwhopwater mixture yields 5- in a 3 liter round bottom, 3-necked flask cooled in an amino 3 h l 7 lfa yl 1 2,4 be'nzothiadia. ice bath. Sodium chloride (350 g.) is added portioni -1,1-di i d i wise over a period of 1-2 hours. and the mixture then EXAMPLE 3 heated gradually in an oil bath to C. After 3 hours V at ISO- C., the flask is cooled thoroughly in an ice -P Py f y 2. 9 2 z -Ll bath and the contents treated with a literof cold water. i x d i The product is extracted with ether, the extract washed 7 By replacing the acetic anhydride employed in Example minutes.

v beuZothiadiazine-l l-dioxide.

EXAMPLE 6-amino-4-methyl-7-sulfamyl-1,2,4-benzothiadiazine-1 ,1

dioxide I Step a.-l3y replacing the m-chloroaniline employed in Example 1, step a, by an equimolar quantity of 3-nitro- N-methylaniline and chlorosulfonating by substantially the same procedure described in Example 1, step a, there is obtained 5-nitro--N-methylaniline-Z,4-disulfonyl chloride which, when treated with ammonium hydroxide by the process also described in Example 1, step a, is convetted to the corresponding 2,4-di'sulfamyl-5-nitro-N- methylaniline.

Step b.-By replacing the 5-nitro-2,4-disulfamylaniline employedin Example 1, step b, by an equimolar quantity of 2,4-disulfamyl-S-nitro-N-methylaniline, obtained as described above, and following substantially the same procedure described in step b of Example 1, there is obtained 4 methyl 6 nitro 7 -sulfamyl 1,2,4 benzothiadiazine-1,l-dioxide.

Step c.By replacing the 6-nitro-7-sulfamyl-1,2,4- benzothiadiazine-l,l-dioxide employed in Example 1, step c, by an equimolar quantity of the product obtained in step b above, and following substantially the same procedure described in step c of Example 1, there is obtained 6-amino-4-methyl-7-sulfamyl-1,2,4-benzothiadi- I azine-1,1-dioxide.

Example 1, step a, by an equimolar quantity of 4-chloro 3-nitroaniline and following substantially the same procedure described there for chlorosulfonating the m-nitroaniline, there is obtained 2-amino-5-chloro-4-nitro- .benzenesulfonyl chloride which is extracted with ether,

the extract washed with water, and then dried over sodium sulfate. After removal of the ether on the steam bath, the residual product is cooled in an ice bath and,

treated with 150 ml. of 40% aqueous methylamine in a 2 liter Erlenmeyer flask. The mixture is heated on the steam bath for one hour, cooled, and the product collected on the filter, washed with water and dried. Upon crystallization from dilute alcohol, 4-chloro-2-(N- methylsulfamyl)-5-nitroaniline is obtained.

Step b.A mixture of 10 g. of the thus obtained 4- chloro-2-(N-methylsulfamyl)5-nitroaniline and 25 ml. of ethyl orthoformate is heated at. 125135 C. for 30 7-chlor0-2-methyl-6-nitr0-1,2,4-benzothiadiazine 1,1 dioxide.

Step c.--A solution of 2.7 of thethus obtained product in 600 ml. of a 50% alcohol-water mixture is shaken in an atmosphere of hydrogen in the presence of 400 ml. of platinum oxide catalyst and the reduction carried out by substantially the Same proceduredescribed in Example 1, step c, yielding 6-amino-2-methyl-1,2,4-

The solvent then is removed by distillation in vacuo and the residue crystallized from alcohol to give Step d.- The thus obtained cyclized product is treated with chlorosulfonic acid and heated on the steam bath for 2 hours, cooled, and poured onto ice. Treatment of the product with 28% ammonium hydroxide yields 6-amino-2-methyl-7-sulfamyl-1,2,4-benzothiadiazine 1,1- dioxide.

EXAMPLE 7 6-amin0-2-methyl-7-sulfamyl-I,2,4-benz0thiadiazine-1,

l-dioxide Step a.-A solution of 25.6 g. of 2-(N-methylsulfamyl)-4-chloro-5-nitroaniline (obtained as described in Example 6, step a) in 400 ml. of ethanol is heated under reflux for /21 hour with a solution of g. of sodium sulfite in 150 ml. of water. The reaction mixture is cooled in an ice bath and the sodium 4-amino-5-(N- methylsulfamyl)-2-nitrobenzenesulfonate which crystallizes is collected on the filter and dried.

Step b.-An equimolar quantity of the thus obtained product is substituted for the m-chloroaniline employed in Example 1, step a, and substantially the same procedures described in Example 1, steps a and b are followed to produce Z-(N-methylsulfamyl)-5-nitro-4-sulfamylaniline.

Step c.The product obtained in step b is heated at 5 between about 125-135 C. with an excess of ethyl orthoformate for about 30 minutes. The solvent then. is removed by distillation in vacuo and the residue crystallized from alcohol to give Z-methyl-6-nitro-7-sulfamyl- 1,2,4-benzothiadiazine-l,l-dioxide.

Step d.-A solution of the thus obtained product in 600 ml. of a 50% alcohol-water mixture is shaken in an atmosphere of hydrogen in the presence of 400 ml. of platinum oxide catalyst and the reduction carried out by substantially the same procedure described in Example 1, step 'c, yielding G-amino-2-methyl-7-sulfamyl- 1,2,4-benzothiadiazine-1,1-dioxide.

EXAMPLE 8 6-amin0-4-ethyl-7-sulfamyl-1,2,4-benzothiadiazine-1,1-

dioxide By replacing the 3 -nitro-N-methylaniline employed in Example 5, step a, by an equimolar quantity. of 3-nitro- N-ethylaniline and following substantially the same procedures described in steps a through c of Example 5, there is obtained 6-amino-4-ethyl-7-sulfamyl-l,2,4benzothiadiazine-Ll-dioxide' EXAMPLE 9 6-amino-3,4-dimethyl-7-sulfamyl-I,2,4 benz0thiadiazine- 1,1 -dioxide EXAMPLE 1O 6-amino-3-phenyl-7-sulfamyl-I,2,4-benzothiadiazine- 1,1-di0xide By substituting an equal volume of benzoyl chloride for the acetic anhydride employed in Example 2, step a, and following substantially the same procedures described in steps a and b of Example 2, there is obtained 6-amino- 3-phenyl-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide.

' 9 EXAMPLE 11 6-amin0-3-benzyl-7-sulfamyl-1,2,4-ben2othiadiazine- 1 ,1 -dioxide By substituting an equal volume of phenylacetyl chloride for the acetic anhydride employed in step a, Example 2, and following substantially the same procedures described in steps a and b of Example 2, there is obtained 6 amino 3 benzyl 7 sulfamyl 1,2,4 benzothiadrazine- 1 l-dioxide.

EXAMPLE 12 7-amin0-6-sulfarnyl-1,2,4-benzothiadiazine-1 ,1 -dixide Step a.A solution of 17.2 g. of 3-chloro-4-nitroaniline in 300 ml. of ethanol is heated under reflux for h to 1 hour with a solution of 30 g. of sodium sulfite in 150 ml. of water. The reaction mixture is cooled in an ice bath and the sodium -amino-2-nitrobenzenesulfonate which crystallizes is collected on the filter and dried.

Step b.-An equimolar quantity of the thus obtained product is substituted for the m-chloroaniline employed in Example 1, step a, and substantially the same procedures described in Example 1, steps a and b are followed to produce 7-nitro-6-sulfamyl-1,2,4 benzothiadiazine1,l-dioxide.

Step c.--The thus obtained product is reduced by following the same procedure described in Example 1, step 0, thus yielding 7-amin0-6-sulfamyl-1,2,4-benzothiadia zine-1,l-dioxide.

EXAMPLE 13 Sodium salt of 6-amino-7-sulfamyl-1,2,4-benz0thiadiazine-I ,1 -di0xide 6-amino-7-sulfamyl 1,2,4 benzothiadiazine-1,l-dioxide, obtained as described in Example 1, is dissolved in alcoholic sodium hydroxide and the solvent then evaporated in vacuo yielding the sodium salt of 6-amino-7- sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide.

The 6-amino-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide is granulated with the starch paste and while moist passed through a No. 14 screen, dried at 45 C. for 20 hours and then passed 3 times through a No. 14 screen. The starch then is passed through a No. 90 bolting cloth onto the granulation and all ingredients are blended thoroughly. Then the magnesium stearate is passed through a No. 90 bolting cloth onto the granulation and these ingredients are blended after which the granulation is compressed into tablets using flat, bevelled, scored punch having a thickness of 020510.005" yielding 1,000 tablets, each weighing 0.543 gram and having a hardness of 6 kgms. measured by the Monsanto Chemical Company tablet hardness tester apparatus, and a disintegration time of 5 minutes when tested on the U.S.P. tablet disintegrating apparatus (U.S. Pharmacopeia, 15th edition, page 937).

Tablets prepared as described above are suitable for oral administration at a dosage regimen individualized for each patient by his physician.

While the above examples describe the preparation of certain illustrative compounds illustrated by the structure in column 1, and a certain specific dosage form suitable 10 for administering the novel compounds of this invention in human therapy, it is to be understood that the invention is not to be limited by these examples or by the specific reaction conditions described for the preparation of the compounds or by the specific ingredients included in the pharmaceutical preparation but is understood to embrace variations and modifications falling within the scope of the appended claims.

This application is a continuation-impart of my copending US. patent application, SerialNo. 582,082, filed May 2, 1956, now Patent No. 2,809,194. 1

What is claimed is: v l v 1. Benzothiadiazine-1,1-dioxide compounds selected from the class consisting of compounds having one of the general structures and tautome'ric isomers thereof, and their non-toxic alkali metal salts, wherein R is selected from the group consisting of hydrogen and lower alkyl radicals; and R is selected from the group consisting of hydrogen, lower alkyl, phenyl, and benzyl radicals.

2. Benzothiadiazine-1,1-dioxides represented by the general tautomeric structures 4 -11 HgN l 2N s/ zNSO:

and

3. 6-amino-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide.

4. Benzothiadiazine-l,1-dioxides represented by the general tautomeric structures i N tn-R" HzN i zNSOz and 4 R1 rN 2NH iNSOz wherein R is a lower alkyl radical.

eral structure 5. Benzothiadiazine-l,l-dioxides represented by the genwherein R is a lower alkyl radical.

6. Benzothiadiazine-1,1-dioxides represented by the general structure wherein R is a lower alliyl radical.

7. Benzothiadiazine-1,1-dioxides represented by the general structure wherein the chlorine and nitrogroups are attached in ortho position to one another, to form the corresponding compound containing a sulfonylchloride substituent in the 2-position, which compound then is heatedwith an excess of two equivalents of a lower-alkylamine to form the corresponding Z-N-lo-Wer alkyl sulfarnyl derivative which is heated with ethyl orthoformate to form the corresponding cyclized product containing a LZ-lower alkyl substituent; which compound is hydrogenated in the presence of a catalyst, and' the 2-alkyl-amino-1,2,4-benzothiadiazine-1,1-'dioxide thus obtained is heated with chlorosul- 1 fonic acid to form the sulfonyl chloride derivative which N 25 is reacted with ammonia to yield 2-(lower alkyl)-amino- BIN L sulfamyl-l,2,4-benzothiadiazine-1,l-dioxide;- i N O s References Cited in the file of this patent s 0 o UNITED STATES PATENTS V wherein R and R respectively is a lower alkyl radical. 30 2,809,194 Novello Oct. 8, 1957 

1. BENZOTHIADIAZINE-1,1-DIOXIDE COMPOUNDS SELECTED FROM THE CLASS CONSISTING OF COMPOUNDS HAVING ONE OF THE GENERAL STRUCTURES 